The role of the human tumour suppressor CYLD in Drosophila

The cylindromatosis gene cyld encodes a tumour suppressor that is mutated in tumours of human skin appendages (cylindromas). Cell culture studies have shown that the CYLD protein is a deubiquitinating enzyme, which negatively regulates NF-KB and JNK signalling in mammals. Despite extensive research in the past few years, its developmental and physiological functions as well as its rolein tumourigenesis remain poorly understood. To further the understanding of the in vivo functions of CYLD, its Drosophila homologue dCYLD was investigated in an effort to establish a simpler and genetically tractable animal model. dCYLD also has deubiquitinating enzymatic activity, is broadly expressed during development and can be found in a wide range of adult tissues. My results demonstrate that dCYLD inhibits the Imd pathway, a Drosophila NF-KB-like signal transduction pathway. During pupal development, this regulative function seems to limit the release of Eiger, a TNF-like ligand triggering the Drosophila JNK pathway. Correspondingly, dCYLD deficiency is associated with conditional lethality of pupae due to JNK activation by Eiger.. Furthermore, dcyld homozygotes exhibit a pronounced susceptibility to infection with both Gram(-) and Gram(+) bacteria. Other phenotypes include altered fat body morphology and increased triglyceride levels. These results indicate that dCYLD is involved in a broad range of functions, highlighting its importance in the control of transcriptional regulation by NF-KB. In addition, its mechanistically novel role in the regulation of JNK pathway activation may provide new insights into the genesis of human cylindromas.EThOS - Electronic Theses Online ServiceGBUnited Kingdo